Until recently, it had been widely assumed that protein folding is thermodynamically controlled. Studies of ?-lytic protease in our laboratory have directly challenged this hypothesis. ?-lytic protease (?LP) is synthesized with a 166-residue N-terminal pro region (Pro). In the absence of Pro, denatured aLP folds in vitro to an intermediate, molten globule-like state. This intermediate is in fact thermodynamically more stable than the native state and converts very slowly to the native state. With the addition of Pro, the folding reaction is accelerated by more than 109. Pro catalyzes the folding reaction by directly stabilizing the folding transition state, facilitating the conversion of the intermediate to the kinetically trapped, metastable native state. We are in the process of solving the X-ray crystal structure of the ?LP/Pro product complex. Knowledge of the details of how Pro interacts with ?LP may provide clues to their interaction in the folding transition state. This in turn will yield insight into the source of transition state stabilization and advance our understanding of the mechanism of Pro-catalyzed protein folding.